Regenerative medical technologies include methods that repair or replace diseased or defective tissues or organs. Tissue engineering is the application of the principles and methods of engineering and the life sciences to the development of biological substitutes to restore, maintain or improve function of bodily structures and tissues, or to selectively promote the destruction of undesired tissues. It involves the development of methods to build biological substitutes as supplements or alternatives to whole organ or tissue transplantation, or the development of strategies to manipulate tissues in vivo. The use of living cells and/or extracellular matrix (ECM) components in the development of implantable parts or devices is an attractive approach to restore or to replace function.
The advent of nanotechnology has ushered in a new era of tissue and organ reconstruction. Fine control of the extracellular nanoenvironment allows for increased targeting of cell placement and therapeutic delivery, amplified by cell encapsulation and implantation. Small changes in the cellular environment can lead to the activation of the apoptotic pathway or even necrosis of the cells weeks after implantation. The successful storage and implantation of stem cells pose significant challenges for tissue engineering in the nervous system, in addition to the challenges inherent to neural regeneration e.g., formation of the glial scar that surrounds the lesions caused by traumatic brain injury (TBI) or stroke, and the cystic cavities in spinal cord injury (SCI) (Fawcett and Asher, Brain Res. Bull., 49:377-391 (1999)).
Scaffolds play a central role in organ regeneration (Ellis-Behnke, et al., Curr. Pharm. Des., 13:2519-2528 (2007)). They act as a template and guide for cell proliferation, cell differentiation and tissue growth, as well as control the release of drugs at rates matching the physiological need of the tissue (Langer, Nature, 392 (Supp):5-10 (1998)). The surface of the scaffold provides a substrate for cell adhesion and migration, which can influence the survival of transplanted cells or the invasion of cells from the surrounding tissue. Although many promising strategies have been developed for controlling the release of drugs from scaffolds, there are still challenges to be addressed for these scaffolds to serve as successful treatments (Holmes, et al., Proc. Natl. Acad. Sci. USA., 97:6728-6733 (2000); Schmidt and Leach, Ann. Rev. Eng., 5:295-347 (2003); Willerth and Sakiyama-Elbert, Adv. Drug. Deliv. Rev., 60:263-276 (2008); Zhang, et al., Biomaterials, 16:1385-1393 (1995); Zhang, et al., Proc. Natl. Acad. Sci. USA, 90:3334-3338 (1993)). For example, the precise placement of the cells into the scaffold must be addressed to prevent migration of the cells from the scaffold before it has been repopulated. Additionally, the ability of the scaffold to allow cells to migrate into it, in order to reconstitute the tissue from the surrounding area, must be addressed. Lastly, the prevention of the acidic breakdown of the cell scaffold, which results in an adverse environment for cell growth, remains problematic. Many types of scaffolds, utilizing a wide range of materials, have been used for the regeneration and repair of the nervous system (Takenaga, et al., Cell Transplant., 16:57-65 (2007); Zhang, Nat. Biotechnol., 21:1171-1178 (2003)). In treating TBI or SCI, drug delivering scaffolds may need to be combined with cell transplantation to obtain functional recovery (Willerth and Sakiyama-Elbert, Adv. Drug Deliv. Res., 60-263-276 (2008)).
To successfully reconstruct tissues and organs, cellular therapies must integrate into the injury site. For central nervous system (CNS) injuries, regeneration is not just replacement but regrowth of the lost neuronal circuitry, followed by promotion of plasticity of the spared and regenerated neurons (Ellis-Behnke, et al., Proc. Nat. Acad. Sci. USA, 103:5054-5059 (2006); Willerth and Sakiyama-Elbert, Adv. Drug Deliv. Res., 60-263-276 (2008)). PC12 cells change branching patterns and process densities depending on the modulus of the scaffold. If the modulus is less than 10 pascals (Pa), branching decreases along with neurite density, whereas when the modulus is between 100 Pa to 1000 Pa branching is more pronounced and the cells exhibit process outgrowth that is longer, with more cells expressing neurite markers (Leach, et al., J. Neural Eng., 4:26-34 (2007); Pelham and Wang, Proc. Natl. Acad. Sci. USA, 94:13661-13665 (1997)). Other issues associated with human embryonic stem cell lines include the use of culture systems that rely on serum or feeder cell layers. There is a need for the development of culture methods for human stem cells that involve chemically defined media (Willerth and Sakiyama-Elbert, Adv. Drug Deliv. Res., 60-263-276 (2008)). The end goal for cellular therapies is to create cell lines for transplantation that do not require immune suppression of the patient (Willerth and Sakiyama-Elbert, Adv. Drug Deliv. Res., 60-263-276 (2008)).
Therefore, it is an object of the invention to provide compositions and methods that generate functional biological structure de novo or regenerate organs in situ, as well as to restore or supplement tissue function.
It is another objective to provide compositions and methods that modulate the differentiation, morphology and/or proliferation of cells, preferably stem cells.